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Sci. 265, against harmful mutations in large sexual 221–225. E-mail: [email protected] and asexual populations. Genet. Res. 40, 9. Chippendale, A.K., Gibson, J.R., and 325–332. Rice, W.R. (2001). Negative genetic 7. Carius, H.J., Little, T.J., and Ebert, D. correlation for adult fitness between DOI: 10.1016/j.cub.2005.07.001 Neurotransmission: Emerging requires a sustained (5–10 minute) activation of presynaptic CB1 Roles of Endocannabinoids receptors [12,13]. Modulation of synaptic transmission by endocannabinoids Postsynaptic release of endocannabinoids can inhibit presynaptic was initially studied using non- neurotransmitter release on short and long timescales. This retrograde physiological methods, such as inhibition occurs at both excitatory and inhibitory synapses and may seconds-long depolarization or provide a mechanism for synaptic gain control, short-term associative application of high-affinity plasticity, reduction of synaptic crosstalk, and metaplasticity. metabotropic receptor agonists, to evoke endocannabinoid release. Anatol C. Kreitzer [3], which can then diffuse to But the modulatory role of adjacent presynaptic terminals and endocannabinoids during normal Endocannabinoids are a class of suppress neurotransmitter release synaptic activity was not known. lipophilic signaling molecules that for tens of seconds [4,5]. A similar Brenowitz and Regehr [14] found are synthesized and released by phenomenon has been observed that depolarization-evoked postsynaptic neurons in response at excitatory synapses and is endocannabinoid release from to increases in intracellular known as depolarization-induced cerebellar Purkinje cells requires calcium levels or activation of suppression of excitation (DSE) [6]. high levels of intracellular calcium, metabotropic receptors. As their In addition to depolarization- suggesting that depolarization name implies, endocannabinoids mediated calcium entry, activation alone may not play a prominent activate the same G protein- of metabotropic glutamate and role in the release of coupled receptors as the active acetylcholine receptors can drive endocannabinoids under normal compounds in Cannabis sativa endocannabinoid release through physiological conditions. (marijuana). The primary neuronal a separate biosynthetic pathway Another study, in the subtype of this receptor, known as [7,8]. Receptor-mediated cerebellum, by Maejima et al. [7] CB1, is widely distributed in the endocannabinoid production found that 50–100 Hz activation mammalian brain and is expressed requires phospholipase Cβ (PLCβ) of excitatory parallel fiber in presynaptic terminals, where it [9], an enzyme which is activated synapses onto a Purkinje cell can inhibit neurotransmitter by G protein signaling and could yield a transient 10–15% release. The endocannabinoid modulated by calcium. Thus, heterosynaptic inhibition of system is thus well suited for rapid increases in intracellular calcium neurotransmitter release at retrograde signaling across can directly stimulate excitatory climbing fiber activated synapses. Recent endocannabinoid production via synapses on the same Purkinje studies are beginning to elucidate PLD, while at the same time cell. This synaptically evoked the physiological roles of this increasing the efficacy of inhibition was mediated by signalling. receptor-driven PLCβ-mediated endocannabinoids and required Retrograde signaling by biosynthesis. This receptor-driven activation of postsynaptic endocannabinoids was first release is critical for metabotropic glutamate observed in the cerebellum and endocannabinoid-mediated long- receptors, an early indication that hippocampus as a phenomenon term depression (LTD) of receptor-driven endocannabinoid termed depolarization-induced neurotransmitter release at both release is critical under more suppression of inhibition (DSI) [1,2]. excitatory and inhibitory synapses physiological conditions. DSI is a short-term depression of [10–12]. Although LTD can be The first systematic study of neurotransmitter release that can elicited by short (1 second) synaptically evoked be elicited by postsynaptic presynaptic bursts sufficient to endocannabinoid release was that depolarization sufficient to activate activate postsynaptic of Brown et al. [15], again in the voltage-sensitive calcium metabotropic glutamate cerebellum. Following brief trains channels. Increases in intracellular receptors, the subsequent of parallel fiber stimulation, they calcium levels stimulate the receptor-driven endocannabinoid observed a transient ~50% production of endocannabinoids, release may feature slower inhibition of neurotransmitter perhaps via phospholipase D (PLD) kinetics since LTD induction release from parallel fibers, which Current Biology Vol 15 No 14 R550 was mediated by nor climbing fiber stimulation promoting synaptic endocannabinoid release from prior to a parallel fiber burst independence. Purkinje cells. Varying the yields significant While the suppression of frequency of parallel fiber endocannabinoid release. excitatory synapses by stimulation or the number of However, when climbing fiber endocannabinoids provides a stimuli in a train altered the stimulation occurs during or mechanism for limiting synaptic magnitude of this inhibition, which immediately after a parallel fiber excitation, suppression of arose largely from metabotropic burst, a short-term depression of inhibitory synapses may play a glutamate receptor-driven neurotransmitter release is very different role — regulating endocannabinoid release. observed. Thus, Purkinje cell the induction of LTP at nearby Importantly, this retrograde synapses can act as coincidence excitatory synapses. In the signaling was found to be detectors, releasing hippocampus, endocannabinoid- synapse specific — only the endocannabinoids at only those mediated suppression of GABA activated synapses were parallel fiber synapses that are release onto CA1 pyramidal inhibited, whereas other nearby simultaneously active with neurons occurs on both short and synapses were unaffected. climbing fiber firing, giving rise to long timescales. Depolarization of The larger magnitude of a novel form of short-term CA1 pyramidal neurons elicits homosynaptic parallel fiber associative plasticity. DSI, a transient suppression of inhibition relative to A new study by Marcaggi and inhibitory synapses lasting tens of heterosynaptic climbing fiber Attwell [18] provides a different seconds. Carlson et al. [19] found inhibition following high frequency perspective on the physiological that a short excitatory presynaptic parallel fiber stimulation can be role of endocannabinoid signaling. burst, normally ineffective at explained by the different In the studies of synaptically inducing LTP, could elicit LTP if sensitivities of parallel fiber and activated endocannabinoid delivered during DSI. climbing fiber neurotransmitter signaling described above, Similarly, an endocannabinoid- release to presynaptic parallel fiber synapses were mediated LTD of inhibitory modulation, as well as by the stimulated by an electrode placed neurotransmitter release (iLTD) spatial segregation of these in the molecular layer of cerebellar onto CA1 pyramidal neurons [20] synapses on the Purkinje cell cortex. This method yields a also facilitates the induction of dendritic tree. Thus, ‘dense’ pattern of synaptic LTP at nearby excitatory endocannabinoids may play an activation in which nearly all the synapses. Because iLTD is important role in short-term parallel fiber synapses in a synapse-specific and long-lasting, synaptic gain control. If some particular Purkinje cell dendritic the subsequent priming of LTP is excitatory synapses onto a region are active and glutamate also long-lasting and can be postsynaptic cell become very spillover can effectively activate restricted to synapses on a small active, local endocannabinoid perisynaptic metabotropic region of dendrite. release can reduce their strength, glutamate receptors, thereby Endocannabinoids thus play ensuring that a small set of active enhancing endocannabinoid diverse physiological roles in synapses will not control release. But it is not known different cell types and brain postsynaptic firing. whether such dense synapse regions. Their specific role may Although high frequency parallel activation occurs in vivo. vary depending upon temporal fiber trains give rise to retrograde To test whether sparse synaptic and spatial patterns of neuronal inhibition by endocannabinoids, in activation can also elicit activity, regulation of glutamate vivo firing of cerebellar granule